Oleg Gluz, MD, is chief physician of Breast Cancer Niederrhein

Dr Gluz on Ongoing Evaluations of De-Escalated Neoadjuvant Therapy in HR+/HER2+ Breast Cancer

"There are several ongoing trials worldwide [in patients with HR-positive, HER2-positive early breast cancer]…and our group is performing the WSG-ADAPT-HER2-IV trial to compare 12 weeks of…paclitaxel plus double anti-HER2 blockade vs antibody-drug conjugates like trastuzumab deruxtecan given for 12 weeks. We have to wait for results [from these studies] to figure out the best treatment for our patients."

Oleg Gluz, MD, chief physician of the West German Study Group at the Breast Center Niederrhein, discussed the continued investigation of de-escalated chemotherapy plus anti-HER2 blockade doublets for patients with hormone receptor (HR)–positive, HER2-positive early breast cancer.

, findings from the phase 2 WSG-TP-II trial (NCT03272477) highlighted the potential of de-escalated therapeutic approaches for patients with stage I to III HR-positive, HER2-positive breast cancer. The trial evaluated the efficacy and tolerability of 2 neoadjuvant regimens administered over 12 weeks: endocrine therapy combined with trastuzumab (Herceptin) and pertuzumab (Perjeta), and a chemotherapy-based regimen of paclitaxel plus trastuzumab and pertuzumab. Both regimens showed high clinical activity and were well tolerated, supporting further exploration of de-escalation strategies in this disease subtype.

Multiple ongoing trials are continuing to investigate optimal de-escalated treatment approaches in this setting, Gluz stated. In the United States, the phase 2 CompassHER2-pCR (NCT04266249) and phase 3 CompassHER2 RD trials (NCT04457596) are evaluating the effects of 12-week chemotherapy-based regimens in broader patient populations, he detailed. Meanwhile, the phase 2 PHERGAIN-II trial (NCT04733118) is being conducted in Europe and is assessing a chemotherapy-free approach using pertuzumab, trastuzumab, and endocrine therapy in patients with small tumors, Gluz shared.

To build on this emerging evidence, the WSG collaborative group is conducting the phase 2 WSG-ADAPT-HER2-IV trial (NCT05704829), which directly compares 12 weeks of paclitaxel plus dual HER2 blockade with 12 weeks of the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu), Gluz continued. The goal of this trial is to determine whether newer targeted therapies may serve as alternatives to chemotherapy in the neoadjuvant setting, he explained. Collectively, these trials aim to refine treatment strategies by balancing efficacy with toxicity, with the ultimate objective of identifying the most appropriate and least burdensome therapies for patients with early-stage HR-positive, HER2-positive breast cancer, Gluz concluded.

Videos

Oleg Gluz, MD, discusses research assessing de-escalated chemotherapy and endocrine therapy combinations in HR-positive, HER2-positive early breast cancer.

Dr Gluz on Predictive Biomarkers for pCR With De-Escalated Chemo in HER2+ Breast Cancer

"There were several markers which are clearly predictive for pCR after 12 weeks [with de-escalated chemotherapy in patients with HR+ HER2+ early breast cancer]. For example, HER2 expression was found to be a clear predictive marker."

Oleg Gluz, MD, chief physician of Breast Cancer Niederrhein, 

discusses efficacy findings from the phase 2

 (NCT03272477) across subgroups of patients with hormone receptor–positive, HER2-positive early breast cancer who received a de-escalated chemotherapy regimen in the neoadjuvant setting.

WSG-TP-II evaluated the efficacy of neoadjuvant endocrine therapy in combination with trastuzumab (Herceptin) and pertuzumab (Perjeta) vs de-escalated chemotherapy plus trastuzumab and pertuzumab in patients with hormone receptor–positive, HER2-positive early breast cancer. Results from this study showed that the incidence of early pathologic complete responses (pCRs) was higher in patients from the de-escalated chemotherapy arm (n = 100) vs the endocrine therapy arm (n = 107), with 57 and 23 pCR cases in each respective arm at 12 weeks. Furthermore, the 5-year event-free survival rates were 94.8% and 92.1% in these respective arms (HR, 1.29; 95% CI, 0.26%-2.32%; 

 = .65). The 5-year overall survival rates were 100% and 97.9%, respectively.

Investigators identified several predictive biomarkers for pCR following 12 weeks of de-escalated chemotherapy, Gluz says. Among these, HER2 expression was confirmed as a strong predictive marker, he notes.

An analysis of survival outcomes revealed no significant differences in prognosis among patient subgroups, he explains. However, baseline characteristics indicated that most patients enrolled in the trial had stage IIA disease, characterized by tumors larger than 2 cm without nodal involvement, or smaller tumors with 1 positive lymph node, he states. Given the prevalence of such cases in clinical practice, these findings suggest that de-escalated chemotherapy could be a viable treatment approach for this patient population, Gluz emphasizes.

Conversely, patients presenting with locally advanced disease, including those with tumors larger than 5 cm or those with more than 4 positive lymph nodes, were underrepresented in the trial, he reports. Given the high tumor burden in these patients, Gluz advises caution when considering chemotherapy de-escalation in this subgroup, as they may not be optimal candidates for this approach.

Oleg Gluz, MD, discusses findings from subgroup analyses of the WSG-TP-II trial of neoadjuvant de-escalated chemotherapy in HER2-positive breast cancer.

Dr Gluz on the Rationale for the WSG-TP-II Trial in HR+/HER2+ Early Breast Cancer

Oleg Gluz, MD, chief physician, Breast Center Niederrhein; West German Study Group, discusses the rationale for launching the phase 2 WSG-TP-II trial (NCT03272477) of neoadjuvant endocrine therapy plus trastuzumab (Herceptin) and pertuzumab (Perjeta) in patients with hormone receptor (HR)–positive, HER2-positive early breast cancer.

rationale for conducting the WSG-TP-II trial

 stemmed from the desire to explore treatment de-escalation strategies for patients with early-stage, hormone receptor-positive, HER2-positive breast cancer, Gluz begins. Traditionally, these patients receive standard neoadjuvant or adjuvant chemotherapy in combination with trastuzumab and pertuzumab for 18 to 24 weeks. However, given the potential adverse effects and burden of chemotherapy, the study, initiated in 2016, evaluated the possibility of safely reducing or eliminating one component of the standard treatment regimen, he reports. The trial compared 2 de-escalated treatment approaches to determine the safest regimen for patients with early-stage breast cancer without compromising efficacy, Gluz notes.

The WSG-TP-II trial was conducted in Germany and randomly assigned patients into 2 arms, he continues. One group (n = 100) received 12 weeks of neoadjuvant endocrine therapy combined with trastuzumab and pertuzumab, andthe second group (n = 107) received 12 weeks of paclitaxel alongside trastuzumab and pertuzumab. Following surgery, patients received 1 year of standard adjuvant endocrine therapy plus trastuzumab and paclitaxel with or without chemotherapy. The study protocol strongly recommended omitting adjuvant chemotherapy for those who achieved a pathological complete response (pCR) after 12 weeks of neoadjuvant treatment, he explains. Patients who did not achieve pCR in the neoadjuvant setting were recommended to receive adjuvant chemotherapy.

This trial demonstrated that 12 weeks of de-escalated neoadjuvant therapy with endocrine therapy or paclitaxel in combination with 1 year of trastuzumab plus pertuzumab is a safe regimen for chemotherapy de-escalation in this population.

Dr Gluz reports receiving honoraria for lectures and/or consulting and travel from Agendia, Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Exact Sciences, Gilead, Lilly, MSD, Molecular Health, Novartis, Pierre Fabre, Pfizer, Roche, and Seagen.

Oleg Gluz, MD, discusses the rationale for investigating neoadjuvant endocrine therapy plus trastuzumab and pertuzumab in HR+/HER2+ early breast cancer.

Oleg Gluz, MD, discusses data from the WSG-TP-II trial of neoadjuvant endocrine therapy plus trastuzumab and pertuzumab in HR+/HER2+ early breast cancer.ER2– breast cancer.

Dr Gluz on Survival Outcomes With De-Escalated Neoadjuvant Regimens in HR+/HER2+ Early Breast Cancercer

Oleg Gluz, MD, chief physician, Breast Center Niederrhein; West German Study Group, discusses survival data from the phase 2 WSG-TP-II trial (NCT03272477) of neoadjuvant endocrine therapy plus trastuzumab (Herceptin) and pertuzumab (Perjeta) in hormone receptor (HR)–positive, HER2-positive early breast cancer.

The WSG-TP II trial is the first prospective, multicenter, randomized study comparing the survival outcomes of two 12-week de-escalated regimens in patients with stages I through III HR-positive, HER2-positive breast cancer: neoadjuvant endocrine therapy plus trastuzumab and pertuzumab vs paclitaxel plus trastuzumab and pertuzumab. The trial's primary goal was to determine if patients could safely omit further adjuvant chemotherapy if they achieved a pathological complete response (pCR) following the 12-week neoadjuvant treatment.

 demonstrated the high efficacy and tolerability of the 12-week regimen, particularly when combining paclitaxel with trastuzumab and pertuzumab, Gluz reports. Notably, pCR rates were higher in patients receiving de-escalated chemotherapy vs those receiving the endocrine therapy regimen, he adds. Across all patients, approximately two-thirds achieved pCR after 12 weeks of treatment, emphasizing the efficacy of the chemotherapy-based approach, Gluz states.

However, long-term survival outcomes were comparable between both treated arms, Gluz continues. The 5-year event-free survival rates were 92.1% vs 94.8% with the endocrine- vs chemotherapy-based regimens, respectively. Respective overall survival (OS) rates for these arms were 100% vs 97.9%. These findings suggest that starting with a de-escalated treatment of endocrine therapy plus double HER2 blockade is safe, and chemotherapy can be reserved for patients who do not respond to the de-escalated regimen, he explains.

Overall, these results suggest that it is safe and feasible to begin treatment with 12 weeks of a fixed chemotherapy backbone plus double blockade in HR-positive, HER2-positive breast cancer, administering chemotherapy only to patient who do not achieve responses with the de-escalated approach, Gluz concludes.

Oleg Gluz, MD, discusses data from the WSG-TP-II trial of neoadjuvant endocrine therapy plus trastuzumab and pertuzumab in HR+/HER2+ early breast cancer.

Oleg Gluz, MD

Articles

Dr Gluz on Ongoing Evaluations of De-Escalated Neoadjuvant Therapy in HR+/HER2+ Breast Cancer

Dr Gluz on Predictive Biomarkers for pCR With De-Escalated Chemo in HER2+ Breast Cancer

Dr Gluz on the Rationale for the WSG-TP-II Trial in HR+/HER2+ Early Breast Cancer

Dr Gluz on Survival Outcomes With De-Escalated Neoadjuvant Regimens in HR+/HER2+ Early Breast Cancerer